title: Effects of cytochrome P-450 inhibitors on the in vivo metabolism of all-trans-retinoic acid in rats.
abstract: This study examines the effects of ketoconazole, R 75 251 and some other cytochrome P-450 inhibitors on the in vivo metabolism of all-trans-retinoic acid (RA) in normal rats. Oral treatment with ketoconazole or R 75 251 (40 mg/kg, -1 hr) reduced the elimination rate of i.v. injected RA from plasma: the half-life of RA increased from 27 min in control-treated animals to 43 min and 76 min after dosing with ketoconazole and R 75 251, respectively. However, neither drug had an effect on the distribution volume of the retinoid. Two hours after i.v. injection of RA, residual plasma levels of the retinoid were 11.2 ng/ml in ketoconazole and 22.7 ng/ml in R 75 251-treated rats. The other P-450 inhibitors, aminoglutethimide, cimetidine, itraconazole, metyrapone and saperconazole, showed no sparing effect on RA elimination: plasma levels of the acid were below 1 ng/ml, as in control-treated animals. Administration of ketoconazole or R 75 251 (40 mg/kg, -2 hr) to rats also enhanced endogenous plasma concentrations of RA. Levels of the retinoid were raised from mostly undetectable values (less than 0.5 ng/ml) to 1.3 +/- 0.1 and 2.5 0.1 ng/ml after treatment with ketoconazole and R 75 251, respectively. These data are indicative of the important contribution of the cytochrome P-450 enzyme system to the in vivo metabolic process of RA. In vivo inhibition of the P-450 pathway not only increased the biological half-life of exogenously administered RA, but also enhanced the endogenous plasma level of this vitamin A derivative.
authors.affiliation: Janssen Research Foundation, Beerse, Belgium.
authors.forename: J P
authors.initials: JP
authors.lastname: Van Wauwe
authors.forename: M C
authors.initials: MC
authors.lastname: Coene
authors.forename: J
authors.initials: J
authors.lastname: Goossens
authors.forename: W
authors.initials: W
authors.lastname: Cools
authors.forename: J
authors.initials: J
authors.lastname: Monbaliu
mesh_terms: D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D007093:Imidazoles; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; C061121:liarozole; D007654:Ketoconazole